Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes

OBJECTIVE - The aim of this study was to test whether vascular reactivity is modified by improving metabolic control and peripheral insulin resistance in type 2 diabetes. RESEARCH DESIGN AND METHODS - In a randomized, double-blind design, we assigned 74 type 2 diabetic patients to rosiglitazone (8 mg/day), metformin (1,500 mg/day), or placebo treatment for 16 weeks and measured insulin sensitivity (euglycemic insulin clamp), ambulatory blood pressure, and forearm blood flow response to 1) intra-arterial acetylcholine (ACh), 2) infra-arterial nitroprusside, 3) the clamp, and 4) blockade of nitric oxide (NO) synthase. RESULTS - Compared with 25 nondiabetic subjects, patients had reduced insulin sensitivity (30 +/- 1 vs. 47 +/- 3 mumol (.) min(-1) (.) kg fat-free mass(-1); P < 0.001) and reduced maximal response to ACh (586 42 vs. 883 81.%; P < 0.001). Relative to placebo, 16 weeks of rosiglitazone and metformin similarly reduced fasting glucose (-2.3 +/- 0.5 and -2.3 +/- 0.5 mmol/l) and HbA(1c) (-1.2 +/- 0.3 and -1.6 +/- 0.3%). Insulin sensitivity increased with rosiglitazone (+6 +/- 3 mumol (.) min(-1) (.) kg fat-free mass(-1); P < 0.01) but not with metformin or placebo. Ambulatory diastolic blood pressure fell consistently (-2 +/- 1 mmHg; P < 0.05) only in the rosiglitazone group. Nitroprusside dose response, clamp-induced vasodilatation, and NO blockade were not affected by either treatment. In contrast, the slope of the ACh dose response improved with rosiglitazone (+40% versus baseline, P < 0.05, +70% versus placebo, P < 0.005) but did not change with either metformin or placebo. This improvement in endothelium-dependent vasodilatation was accompanied by decrements in circulating levels of free fatty acids and turner necrosis factor-alpha. CONCLUSIONS - At equivalent glycemic control, rosiglitazone, but not metformin, improves endothelium dependent vasodilatation and insulin sensitivity in type 2 diabetes.